Project Summary After successful clearance of an infection, a significant number of memory T cells remain in both lymphoid and non-lymphoid tissues to protect against re-infection. Tissue-resident memory T (TRM) cells are a population of memory T cells localized to non-lymphoid tissues without continuous re-circulation. In adult human and immunized mice, there are large number of TRM cells localized to a variety of organs that are often targets of autoimmune and/or inflammatory disorders, such as the kidney, liver, brain, skin and gastrointestinal tract. However, the connection between TRM cells and autoimmune/ inflammatory disorders remains largely elusive. Whether and how TRM cells are involved in autoimmune and/or inflammatory diseases are unclear. Circulating memory T cells respond to both antigen-specific and antigen-non-specific stimuli. It is well established that non-specific inflammation induce rapid and NK cell-like responses from circulating memory CD8+ T cells to provide immediate protection against bystander infections. Cognate antigen induces robust response of TRM cells. How TRM cells respond to antigen-non-specific bystander inflammation remains unknown. Considering that most TRM cells reside in vital tissues, antigen-non-specific response of TRM cells may lead to unwanted tissue damage and initiate or accelerate autoimmune or inflammatory disorders. Our preliminary findings have demonstrated that after viral infection, the responsiveness to bystander inflammation is specifically decreased during TRM cell maturation. This step of TRM cell maturation is dependent on transforming growth factor-? (TGF-?) signaling to TRM cells. However, the transcription networks downstream of TGF-? signaling remain unknown. We have identified five transcription factors that are dynamically regulated in a TGF-?-dependent manner during TRM maturation. In the current proposal, we will determine the role of these five candidate transcription factors during TRM cell maturation. Further, using both gain-of-function and loss-of-function approaches, we will determine whether disrupted TRM cell maturation leads to unwanted collateral tissue damage during un-related bystander infection. Together, we propose to investigate the mechanistic control of a novel maturation step during TRM differentiation following acute infection. Further, we will elucidate the functional consequence of defective TRM maturation during bystander infection-induced tissue damage. We will provide evidence that TRM cells are a critical link between infection and autoimmune/inflammatory disorders.